Crystal modifications of odevixibat

Abstract

The present invention relates to crystal modifications of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat), more specifically crystal modifications 1 and 2 of odevixibat. The invention also relates to a process for the preparation of crystal modification 1 of odevixibat, to a pharmaceutical composition comprising crystal modification 1, and to the use of this crystal modification in the treatment of various conditions as described herein.

The invention claimed is: 
     
       1. A method for treating a liver disease or disorder comprising orally administering to a subject in need of such treatment a therapeutically effective amount of a crystalline hydrate of odevixibat, or a pharmaceutically acceptable salt thereof. 
     
     
       2. The method of  claim 1 , wherein the crystalline hydrate of odevixibat is a channel hydrate. 
     
     
       3. The method of  claim 1 , wherein the crystalline hydrate of odevixibat comprises from about 0 to about 2 moles of water associated with the crystal per mole of odevixibat. 
     
     
       4. The method of  claim 1 , wherein the crystalline hydrate of odevixibat is a sesquihydrate. 
     
     
       5. The method of  claim 1 , wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with peaks at ° 2θpositions 5.6±0.2, 6.7±0.2 and/or 12.1±0.2. 
     
     
       6. The method of  claim 5 , wherein the crystalline hydrate of odevixibat has an XRPD pattern, obtained with CuKα1-radiation, with specific peaks at ° 2θpositions 5.6±0.2, 6.7±0.2 and 12.1±0.2 and one or more of the characteristic peaks: 4.1±0.2, 4.6±0.2, 9.3±0.2, 9.4±0.2 and 10.7±0.2. 
     
     
       7. The method of  claim 5 , wherein the crystalline hydrate of odevixibat has a crystallinity of greater than about 99%. 
     
     
       8. The method of  claim 1 , wherein the liver disease or disorder is selected from the group consisting of: an inherited metabolic disorder of the liver; inborn errors of bile acid synthesis; congenital bile duct anomalies; biliary atresia; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; a secondary defect of BA synthesis; Zellweger's syndrome; cystic fibrosis-associated liver disease; alpha1-antitrypsin deficiency; Alagilles syndrome (ALGS); a primary defect of bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC); benign recurrent intrahepatic cholestasis (BRIC); autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; Down syndrome cholestasis; drug-induced cholestasis; intrahepatic cholestasis of pregnancy; jaundice during pregnancy; intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition associated cholestasis (PNAC); low phospholipid-associated cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); immunoglobulin G4 associated cholangitis; primary biliary cholangitis; cholelithiasis; gall stones; biliary lithiasis; choledocholithiasis; gallstone pancreatitis; Caroli disease; malignancy of bile ducts; malignancy causing obstruction of the biliary tree; biliary strictures; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload disorders; congenital bile acid synthesis defect type 1 (BAS type 1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; hepatic cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adulthood ductopenia (IAD); idiopathic neonatal hepatitis (INH); non syndromic paucity of interlobular bile ducts (NS PILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid-caused toxicities; viral hepatitis; hepatocellular carcinoma (hepatoma); cholangiocarcinoma; bile acid-related gastrointestinal cancers; and cholestasis caused by tumours and neoplasms of the liver, of the biliary tract and of the pancreas. 
     
     
       9. The method of  claim 8 , wherein the liver disease or disorder is selected from the group consisting of: biliary atresia, ALGS, PFIC, PBC, and PSC. 
     
     
       10. The method of  claim 9 , wherein the liver disease or disorder is biliary atresia. 
     
     
       11. The method of  claim 10 , wherein the biliary atresia is post-Kasai biliary atresia or post-liver transplantation biliary atresia. 
     
     
       12. The method of  claim 10 , wherein the biliary atresia comprises an accumulation of bile acids in the extrahepatic biliary tree. 
     
     
       13. The method of  claim 10 , wherein the biliary atresia comprises an accumulation of bile acids in the intrahepatic biliary tree. 
     
     
       14. The method of  claim 9 , wherein the liver disease or disorder is PFIC. 
     
     
       15. The method of  claim 14 , wherein the PFIC is selected from PFIC Type 1, PFIC Type 2, PFIC Type 3, non-specified PFIC, post-biliary diversion PFIC, and post-liver transplant PFIC. 
     
     
       16. The method of  claim 8 , wherein the liver disease or disorder is pruritus due to cholestasis or jaundice. 
     
     
       17. The method of  claim 8 , wherein the liver disease or disorder is NASH. 
     
     
       18. The method of  claim 1 , wherein treatment of the liver disease or disorder comprises decreasing the level of serum bile acids.